{"id":27746,"date":"2023-10-24T14:33:10","date_gmt":"2023-10-24T18:33:10","guid":{"rendered":"https:\/\/www.med.unc.edu\/biochem\/?p=27746"},"modified":"2023-10-24T15:26:43","modified_gmt":"2023-10-24T19:26:43","slug":"g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/","title":{"rendered":"G9a, a histone methyltransferase, found to regulate translation (Chen lab, Cell Chemical Biology)"},"content":{"rendered":"<h2>Chen lab reports a previously unrecognized function of G9a, a histone methyltransferase, in protein-specific translation during endotoxin tolerance (ET).<\/h2>\n<p>Link to <a href=\"https:\/\/authors.elsevier.com\/a\/1hxvB8jWWJtY2s\">Publication &#8220;Non-canonical function of histone methyltransferase G9a in the translational regulation of chronic inflammation&#8221;<\/a><\/p>\n<p>Muneer, A., Wang, L., Xie, L., Zhang, F., Wu, B., Mei, L., &#8230; &amp; Chen, X. (2023). Non-canonical function of histone methyltransferase G9a in the translational regulation of chronic inflammation.\u00a0<i>Cell Chemical Biology<\/i>.<\/p>\n<p>Congrats to all authors.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-27751 size-full\" src=\"https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/graphical-abstract-2023-Chen-lab.pmg_.png\" alt=\"\" width=\"894\" height=\"656\" srcset=\"https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/graphical-abstract-2023-Chen-lab.pmg_.png 894w, https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/graphical-abstract-2023-Chen-lab.pmg_-300x220.png 300w, https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/graphical-abstract-2023-Chen-lab.pmg_-768x564.png 768w, https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/graphical-abstract-2023-Chen-lab.pmg_-600x440.png 600w, https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/graphical-abstract-2023-Chen-lab.pmg_-560x411.png 560w\" sizes=\"auto, (max-width: 894px) 100vw, 894px\" \/><\/p>\n<p>&nbsp;<\/p>\n<p>Endotoxin-tolerant (ET) macrophage cells have similar molecular\/immunopathological characteristics as chronic inflammation-associated complications including sepsis and ARDS. These extreme responses of host immune system to persistent infection involve (1) suppression of \u201ctolerizeable\u201d pro-inflammatory genes coupled with (2) upregulation of \u201cnon-tolerizeable\u201d anti-microbial (anti-inflammatory) factors that, together, contribute to impaired adaptive immunity and susceptibility to secondary infection with an organ-damaging \u201ccytokine storm\u201d. However, despite significant clinical interest in ET, a unifying molecular mechanism that accounts for these two effects remains elusive.<\/p>\n<p>Prior to this study, the best-understood function of G9a complex during ET was to suppress transcription of select pro-inflammatory genes. Here, we demonstrate that G9a interacts with translation regulators including METTL3, an N6-methyladenosine (m6A) RNA methyltransferase, and activates it to cooperatively upregulate the translation and\/or expression of select m6A-modified mRNAs to promote proliferation of inflammatory cytokine-producing macrophage cells (hyperinflammation), reduce proliferation of CD8+ T cells and impair T cell function (lymphopenia); both major hallmarks of ET related complications. Mechanistically, G9a promotes methyltransferase activity of METTL3 at translational\/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET.<\/p>\n<p>Our translatome proteomics approach identified numerous \u201cG9a-translated\u201d proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. Interestingly, G9a-METTL3-m6A axis accounted for only a subset (~12%) of G9a-translated proteins in ET, suggesting that via interactions with distinct translation regulators other than METTL3, G9a coordinates additional, as yet unknown, mechanisms to facilitate gene-specific translation \u2013 necessitating further investigation.<\/p>\n<p>Altogether, for the first time, we revealed a dual role of G9a in ET pathogenesis through its (a) canonical function in transcriptional repression of pro-inflammatory genes, and its (b) non-canonical\/non-epigenetic function in promoting translation of anti-microbial\/anti-inflammatory factors. More importantly, inhibition of G9a-regulated translation was shown to reverse hyperinflammation &amp; lymphopenia and to hinder proteostasis (i.e., expression, secretion, and\/or turnover) of numerous inflammatory disease-related factors involved in sepsis, ARDS, and COVID-19. Overall, our findings represent an attractive target for host-pathogenesis-dependent therapeutic intervention to treat ET-related chronic inflammatory diseases.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Chen lab reports a previously unrecognized function of G9a, a histone methyltransferase, in protein-specific translation during endotoxin tolerance (ET).<\/p>\n","protected":false},"author":41619,"featured_media":27748,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"layout":"","cellInformation":"","apiCallInformation":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[2],"tags":[10,385,13],"class_list":["post-27746","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news","tag-news_faculty","tag-news_2023","tag-news_students","odd"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>G9a, a histone methyltransferase, found to regulate translation (Chen lab, Cell Chemical Biology) | Biochemistry and Biophysics<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"G9a, a histone methyltransferase, found to regulate translation (Chen lab, Cell Chemical Biology) | Biochemistry and Biophysics\" \/>\n<meta property=\"og:description\" content=\"Chen lab reports a previously unrecognized function of G9a, a histone methyltransferase, in protein-specific translation during endotoxin tolerance (ET).\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/\" \/>\n<meta property=\"og:site_name\" content=\"Biochemistry and Biophysics\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/uncbiochemistryandbiophysics\/\" \/>\n<meta property=\"article:published_time\" content=\"2023-10-24T18:33:10+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2023-10-24T19:26:43+00:00\" \/>\n<meta name=\"author\" content=\"Carolyn Clabo\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@UNC_BCBP\" \/>\n<meta name=\"twitter:site\" content=\"@UNC_BCBP\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Carolyn Clabo\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/\"},\"author\":{\"name\":\"Carolyn Clabo\",\"@id\":\"https:\/\/www.med.unc.edu\/biochem\/#\/schema\/person\/9693a4e0a76e8208ca2105ae25587332\"},\"headline\":\"G9a, a histone methyltransferase, found to regulate translation (Chen lab, Cell Chemical Biology)\",\"datePublished\":\"2023-10-24T18:33:10+00:00\",\"dateModified\":\"2023-10-24T19:26:43+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/\"},\"wordCount\":433,\"publisher\":{\"@id\":\"https:\/\/www.med.unc.edu\/biochem\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.med.unc.edu\/biochem\/news\/g9a-a-histone-methyltransferase-found-to-regulate-translation-chen-lab-cell-chemical-biology\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.med.unc.edu\/biochem\/wp-content\/uploads\/sites\/795\/2023\/10\/Graphical-Abstract-pdf.jpg\",\"keywords\":[\"Faculty &amp; 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